aynaud’s phenomenon is a disorder charac- terized by one or more fingers becoming blanched, cyanotic, and red (often in that order), upon an individual’s exposure to cold stimuli or emotional stress.1 These color changes are attributable to several factors; however, they mainly result from vasospasms of the digital arteries. The disor- der occurs fairly commonly and can have a variety of other presentations, ranging from mild discomfort to severe pain in the affected fingers. It can eventually lead to ulcerations, tissue necrosis, and gangrene. This article reviews the history behind the first description of Ray- naud’s phenomenon and discusses classification of the disorder. The article also reviews issues relating to the disorder’s pathogenesis, clinical features, diagnosis, and treatment. HISTORICAL PERSPECTIVE Maurice Raynaud (1834–1881) was a French physi- cian who trained at the University of Paris. He received a doctoral degree in medicine in 1862 upon complet- ing his thesis entitled “Local Asphyxia and Symmetrical Gangrene of the Extremities.”2 He went on to earn another doctoral degree in letters for historical re- search in medicine and was elected to the Academy of Medicine in 1879. In his thesis, Raynaud described several patients who developed cyanosis and other discolorations of their fin- gers when the digits were exposed to cold. One patient was described as having cyanosis “at the [tips] of the fin- gers” followed by the development of “a vermilion red” discoloration, which occurred every time her hands were exposed to the cold. Another patient had a quite dramatic reaction, which he described as follows: So soon as she allows her hands to be exposed to a rather low temperature the fingers become pale, oedematous, half flexed; they are attacked with painful sensations, numbness, and torpor; shortly afterwards, they become blue, then black, in their whole extent.2 This patient, however, was suspected of having scle- roderma by those who later reviewed Raynaud’s thesis, because she died less than 2 years after the onset of these and other symptoms, including atrophy of the fingers and toes, loss of facial expression, discoloration of the skin, and feebleness. Raynaud believed that the pathogenesis of the phe- nomenon was attributable to a local reflex that mediat- ed the constriction of the digital blood vessels. He car- ried out studies, including a pathologic examination of the digital arteries and experiments involving the inter- ruption of the cervical sympathetic chain, but found that he could not elicit the phenomenon or explain its occurrence in any way other than as a local, possibly neurally mediated reflex. Since that time, more de- tailed descriptions of potential mechanisms involved in the pathogenesis of Raynaud’s phenomenon have been outlined and are discussed later in this article. CLASSIFICATION An instance of Raynaud’s phenomenon has tradi- tionally been classified as Raynaud’s disease when it occurs as a primary disease of unknown cause and as Raynaud’s syndrome when it occurs secondary to a con- nective tissue disease, such as scleroderma.3 This R Dr. Urbano is in general internal medicine, Mount Laurel Primary Care Physicians, Mount Laurel, NJ. www.turner-white.com Hospital Physician September 2001 27 R e v i e w o f C l i n i c a l S i g n s Series Editor: Frank L. Urbano, MD Raynaud’s Phenomenon Frank L. Urbano, MD RAYNAUD’S PHENOMENON Characterized by pallor, cyanosis, and reddening of the fingers (and sometimes other areas of the body). The color changes of the skin are usually precipitated by cold stimuli or emotional stress. method of classification has caused some confusion among physicians, which has led some authors to sug- gest a clearer way of distinguishing cases of Raynaud’s phenomenon4 by using the terms primary Raynaud’s phe- nomenon (PRP) and secondary Raynaud’s phenomenon (SRP). PRP is used to designate Raynaud’s phenome- non that is primary or idiopathic in nature.4 SRP— marked by the same pathophysiology, signs, and symp- toms as PRP—is used to designate Raynaud’s phenomenon resulting from some known underlying disease, medication, or event.4 Diseases associated with SRP are numerous and in- clude scleroderma, systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, and many other vasculitides.4 Other more common conditions that have been associated with SRP include peripheral vascular disease, diabetes mellitus, and carpal tunnel syn- drome. Also, certain medications, such as β-blockers and ergotamine, have been associated with SRP. Occu- pational exposure to hand-transmitted vibration, trau- ma, and certain chemicals may be related to SRP, as well; in one study, approximately 38% of cases of Raynaud’s phenomenon in men were estimated to have arisen from exposure to hand-transmitted vibration.5 However, this incidence was much lower in women. PATHOGENESIS The pathogenesis of Raynaud’s phenomenon is not completely understood. However, it can potentially involve several mechanisms that could give rise to the vasospasms of the digital arteries.6 One mechanism cor- responds to the increased sympathetic nervous system activity observed in patients with Raynaud’s phenome- non. This increased activity is probably due to an in- creased density of α-adrenergic receptors on peripheral blood vessels. This increased density can cause the digital blood vessels to be hyperreactive to sympathetic stimuli. The hyperreactivity could, in turn, lead to the vasospastic attacks in the patients. Also, patients with Ray- naud’s phenomenon have a central nervous system sympathetic baroreceptor reflex abnormality. This abnor- mality can cause exaggerated vasoconstriction of the dig- ital blood vessels when the baroreceptors are activated. Moreover, the vascular endothelium is thought to be involved in the pathogenesis of Raynaud’s phenome- non3,6; patients exhibit both endothelial damage and dysfunction. The damage may be attributable to repeat- ed vasospastic attacks causing ischemic reperfusion injury to the endothelium. This injury causes the re- lease of free radicals and other products that damage the endothelium. Endothelial dysfunction results from a decrease in the vasodilatory chemical nitric oxide. The cause of this decrease is not known, but the effect is a failure of the endothelium to appropriately relax, which results in vasospasms. Neurohormonal factors are also considered to be important in the pathogenesis of Raynaud’s phenome- non. The vasoconstrictor, endothelin-1, is abnormally elevated in patients, and there is a decrease in the num- ber of neurons containing calcitonin gene–related pep- tide (CGRP), a very potent vasodilator. Some recent research has focused on the latter of these compounds7: researchers have observed that there is a specific deficit of CGRP neurons in the digital skin of patients with the disorder. This deficit undoubtedly leads to vasospasms. CGRP neurons have been found in many organs, a fact that may explain the systemic effects observed in some patients with Raynaud’s phenomenon.3 Hematologic abnormalities have also been observed in patients with Raynaud’s phenomenon and may con- tribute to its pathogenesis. Abnormal platelet and leu- kocyte aggregation has been observed. Elevations of the levels of factor VIII–von Willebrand factor antigen and fibrinogen have also been observed, with the level of the former correlating to the severity of the vasospastic attacks. CLINICAL AND LABORATORY CHARACTERISTICS Classically, Raynaud’s phenomenon is associated with 3 specific stages—the so-called triphasic color change—in response to an individual’s exposure cold stimuli (or emotional stress).3 Initially, pallor develops in the fingers; this is caused by vasospasm of the digital arteries and concomitant reduction in blood flow. Next, cyanosis develops; this is caused by pooling of deoxy- genated blood and then flow of this deoxygenated blood through the digital blood vessels.